Extended release compositions comprising as active compound venlafaxine hydrochloride

ABSTRACT

The present invention relates to an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.

The present invention relates to extended release compositions comprising as active compound venlafaxine hydrochloride.

Venlafaxine hydrochloride is an antidepressant having formula (1)

being designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)-ethyl]cyclohexanol hydrochloride or (±)-1-[a](dimethylamino)-methyl]p-methoxybenzyl cyclohexanol hydrochloride, having the empirical formula of C₁₇H₂₇NO₂ hydrochloride and molecular weight of 313.87.

Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/ml in water (adjustment to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient 0.43. EFFEXOR XR, the Brand product, is formulated as an extended release capsule for once-a-day oral administration.

The drug release has so far been controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Known capsules containing venlafaxine hydrochloride comprise amounts equivalent to 37.5 mg, 75 mg, or 150 mg of venlafaxine. The inactive ingredients are mainly cellulose, ethylcellulose, gelatin, hydroxypropylmethylcellulose, iron oxide, and titanium dioxide.

Controlled or extended release dosage forms of medicament are conventionally produced as hydrogel matrix-based tablets. With this technology, the controlled release dosage forms are simply prepared by mixing the active material with the appropriate rate of controlling polymers and then that mixture is compressed into the desired controlled release tablets. The rate-controlling polymers are normally termed as hydrogels. Examples of such polymers are cellulose ethers such as ethyl cellulose or hydroxypropylcellulose. Patents describing preparation methods of such dosage forms are described, for example, in US Patent Specifications 4,966,768 and 4,389,393.

In some cases, for example with very water soluble active materials and with relatively high doses, it is not feasible to produce tablets which enable appropriate control on the drug's release. This is the case, for example with venlafaxine hydrochloride.

In such a case, a suitable approach is encapsulating the drug and producing extended release capsule dosage forms. When preparation of such dosage forms is considered, the preferred way is to mix the active ingredient with at least one binding agent to form a uniform mixture which is later moistened with water or with an appropriate organic solvent to form an extrudable plastic mass, from which small particles, cylindrical in shape (1 mm diameter), of drug/matrix are extruded, chopped into appropriate lengths and converted to spheroids using spheronization equipment. These spheroids are further dried and then film-coated with an appropriate polymer to form a film with the desired release patterns. The most widely used excipient in the extruding process is microcrystalline cellulose in its different grades; usually, water is used for the wetting process.

Polymers widely used for coating are ethyl cellulose or EUDRAGIT (ammonio methacrylate copolymer, type A or B). Water-soluble ingredients are normally mixed with the ethyl cellulose or with other hydrophobic polymers, such as pore forming agents, to assist the control on the drug's release through the hydrophobic coating layer. The water-soluble ingredients, such as hydroxypropylcellulose or polyethylene glycol, may serve as plasticizers as well.

Venlafaxine hydrochloride has so far been formulated into a controlled release dosage form with the ability to provide in a single dose a therapeutic blood serum level of the drug over a twenty four hour period. By this method, tighter plasma therapeutic range control can be obtained and multiple dosing is avoided in this manner. The sharp peaks and troughs in blood plasma drug levels are avoided as well.

With the conventional release dosage forms of venlafaxine hydrochloride (tablets), peak blood plasma levels appeared after 2-4 hrs, in contrast to the extended release dosage forms, when plasma levels of venlafaxine hydrochloride rose after administration for between five to eight hrs (average−6) and then begin to fall through a protracted, substantially linear decrease from the peak plasma level for the reminder of the period, maintaining therapeutic level of the drug during the entire twenty four hours period.

In WO 99/22724 (AHP, Sherman), a detailed description of preparing an encapsulated dosage form (coated spheroids) of venlafaxine hydrochloride is provided. By the method described therein, a spheroid core is prepared by extruding and spheronizing a mixture of the drug with microcrystalline cellulose, and then coating it with an ethyl cellulose hydroxypropylcellulose mixture.

This dosage form provides an extended release product with the following in vitro dissolution specifications: Time (hrs) Average % venlafaxine HCL release 2 <30 4 30-55 8 55-80 12 65-90 24 >80

These dissolution characteristics are pH— and RPM-independent.

In the present invention, an alternative once daily bioequivalent formulation to the innovator's one (EFFEXOR XR, described in WO 99/22724) has been developed.

As already mentioned, with high dose water-soluble product, such as venlafaxine hydrochloride (150 mg), the usual preferred way of encapsulating it is by preparing and coating appropriate beads, using the extrusion spheronization process.

In the present invention, the microencapsulation has been changed, i.e., is being performed by layering the drug over an inert nonpareil core, and then coating it with an appropriate polymeric mixture.

The present invention thus consists in an extended release composition comprising as active compound venlafaxine hydrochloride, in which venlafaxine hydrochloride is coated on a nonpareil inert core, which coated core is then coated with a polymeric layer which enables the controlled release of the venlafaxine hydrochloride.

The composition preferably comprises 30-60% of venlafaxine hydrochloride per weight of the total dosage form.

In a preferred embodiment of the present invention, the venlafaxine hydrochloride is suitably connected to a binder; said binder may be, e.g., polyvinylpyrrolidone (povidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. The composition preferably comprises 0.5%-10% of the binder per weight of the total dosage form.

Advantageously the nonpareil inert core is an inert sugar core, a microcrystalline cellulose, or the like. The composition preferably comprises 30-60% of the core per weight of the total dosage form.

Alternatively, the drug might be sprayed as it is and the water is then used as binding enhancement agent.

Advantageously, the coated core is coated with an isolating/protecting/separating layer, which layer is suitably composed of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, carrageenan, GMS, etc. The composition preferably comprises 0.5-10% of the isolating layer per weight of the total dosage form.

The core or the isolating layer is coated then with an additional polymeric layer which enables the controlled release of venlafaxine hydrochloride. Said additional polymeric layer is composed, e.g., of a hydrophobic polymer mixed with an appropriate hydrophobic or hydrophilic plasticizer. Said polymeric layer is suitably sprayed over the coated nonpareil layer or over the isolating layer.

Appropriate coating polymers are, e.g. EUDRAGIT, cellulose derivatives such as hydroxypropylmethylcellulose, ethyl cellulose, cellulose acetate, etc. Their suitable plasticizers are, e.g., castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phthalate, glyceryl triheptanoate, triethylcitrate, etc.

The coating polymeric layer may also be a wax-based coating.

The composition preferably comprises 2-15% of the hydrophobic polymer per weight of the total dosage form, and preferably 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form.

The above processes are conventional processes that may be performed in a fluidized bed coater with a bottom spraying mechanism.

In the composition according to the present invention, preferably not more than 40% of the drug is released after two hours, not more than 60% released after 4 hours, and not more than 80% after 8 hours.

The compositions obtained are suitably, e.g., filled into hard gelatin capsules or compressed into tablets.

This formulation has an identical in vitro dissolution profile as EFFEXOR XR (see Sherman, WO99/22724). They are not sensitive to any changes in dissolution conditions. It is bioequivalent to EFFEXOR XR 150 mg caps.

The coating process being used to produce the composition according to the present invention is more efficient than the method being used in the Sherman patent. Moreover, it enables the preparation of the drug in a single type of equipment, e.g. a fluidized bed coater.

The present invention will now be illustrated with reference to the following examples, without being limited by them.

The process for preparing the composition according to the present invention is suitably performed as follows (all temperatures are given in degrees centigrade):

-   -   a. When venlafaxine hydrochloride is connected to a binder the         venlafaxine hydrochloride is connected to the binder by methods         known per se.     -   b. Stage 1         -   Coating the nonpareil core with the venlafaxine             hydrochloride (advantageously connected with a binder) is             performed at an inlet temperature of 45-550 (preferably             at 500) at an outlet temperature of 35-450 (preferably at             400).         -   At the end of the spraying process, the composition is dried             for 10 minutes without nozzle with 30 cfm air flow.     -   c. Stage 2         -   The coated core obtained in Stage 1 is coated with the             insulating layer at an inlet temperature of 60°+/−3° at an             outlet temperature of 50°+/−2°.     -   d. Stage 3 (when an insulating layer is present in Stage 2)

The core is coated with a further preliminary layer; the conditions of said coating are: Inlet temp: 50° +/− 2° Outlet temp: 40° +/− 5°

Example No. 1 (Without Binder) Stage 1: Components Nonpareils 25/30 150 gr Venlafaxine hydrochloride 37.5 gr H₂O 150 gr. Stage 2: Components layered pellets from stage 1 150 gr ETHOCEL 45 cp 15 gr METHOCEL 5 cp 1 gr Ethanol BP 300 gr At the end of the spray process the composition is dried for 10 minutes without nozzle with 30 cfm.

Example No. 2 Stage 1: components Nonpareils (inert sugar pellets) 150 gr Povidone K-30 3.3 gr. Venlafaxine hydrochloride 165 gr. Ethanol BP 670 gr. Stage 2: components layered pellets from stage 1 150 gr. ETHOCEL 45 cp 15 gr METHOCEL 5 cp 1 gr Ethanol BP 300 gr The coating process was performed in a “4” fluidized bed coater made by Coating Place Inc. USA.

Example No. 3: Stage 1: components Nonpareils 25/30 150 gr Venlafaxine hydrochloride 37.5 gr Povidone K-30 0.75 gr Ethanol BP 160 gr Stage 2-components layered pellets from stage 1 150 gr EUDRAGIT RS 30 D 150 gr Triethyl citrate 9 gr Glycerol monostearate 2.25 gr Polysorbate 80 1 gr Water 140 gr The coating process was performed in a “4” fluidized bed coater, made by Coating Place Inc. USA.

Example No. 4: Stage 1: components Nonpareils 25/30 150 gr. Povidone K-30 0.75 gr. Venlafaxine-HCL 37.5 gr. Ethanol-BP 160 gr. Stage 2: components pellets from stage 1. 150 gr. EUDRAGIT RS 30 D 150 gr. EUDRAGIT RL 30 D 15 gr. Triethyl citrate 9 gr. Glycerol monostearate 2.25 gr. Polysorbate 80 1 gr Water 140 gr. All processes were performed in a “4” fluidized bed coater, made by Coating Place Inc. USA.

Example no. 5: Stage 1: components Nonpareils 25/30 150 gr. Povidene K-90 4.5 gr. Venlafaxine-HCL 150 gr. Ethanol BP 670 gr. Water 110 gr Stage 2: components pellets from stage 1 150 gr. Povidone K-30 3.75 gr. Ethanol-absolute 60 gr. Stage 3: components Pellets from stage 2 ETHOCEL 100 cp 8 gr. Dibutyl sebacate 0.8 gr. Ethanol-absolute 300 gr.

In the above examples, EUDRAGIT RS 30 D is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1.EUDRAGIT RL 30 D is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2. ETHOCEL is ethyl cellulose and METHOCEL is methyl cellulose. 

1-28. (canceled)
 29. A pH-independent extended release dosage form, comprising: venlafaxine hydrochloride in an amount of 30-60% based on the total weight of the dosage form; said venlafaxine hydrochloride being coated on a nonpareil inert core, said nonpareil inert core comprising 30-60% based on the total weight of the dosage form; the venlafaxine hydrochloride being optionally connected to a binder in a binder amount of 0.5-10% based on the total weight of the dosage form; a hydrophilic polymeric or glycerol monostearate (GMS) layer coating said venlafaxine hydrochloride and comprising 0.5-10% based on the total weight of the dosage form; and a controlled release layer coated over said hydrophilic polymeric or GMS layer, said controlled release layer comprising a hydrophobic polymer optionally mixed with a plasticizer, said hydrophobic polymer comprising 2-15% based on the total weight of the dosage form, and said optional plasticizer, when present, comprising 0.1-2% based on the total weight of the dosage form; said controlled release layer permitting controlled release of the venlafaxine hydrochloride over an approximately 24 hour period.
 30. The unit dosage form of claim 29, wherein at least one of said controlled release layer, said hydrophilic polymeric or GMS layer, and said optional binder, when present, comprises hydroxypropylmethylcellulose.
 31. A pH-independent extended release composition, comprising: a nonpareil inert core; a venlafaxine hydrochloride layer coating said inert core, said venlafaxine hydrochloride comprising 30-60% based on the total weight of the composition; and a hydrophobic polymer layer coating said venlafaxine hydrochloride layer, said hydrophobic polymer layer comprising 2-15% based on the total weight of the composition, said hydrophobic polymer layer enabling controlled release of the venlafaxine hydrochloride over an extended time period.
 32. The composition according to claim 31, further comprising glycerol monostearate (GMS) or a hydrophilic polymer layer coating said venlafaxine hydrochloride layer, said GMS or hydrophilic polymer layer providing at least one function of isolating, protecting and separating the venlafaxine hydrochloride layer from the hydrophobic polymer layer.
 33. The composition according to claim 32, wherein the GMS or hydrophilic polymer layer comprises a polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and carrageenan.
 34. The composition according to claim 32, wherein the GMS or hydrophilic polymer layer is 0.5-10% based on the total weight of the composition.
 35. The composition according to claim 31, wherein the venlafaxine hydrochloride layer further comprises a binder.
 36. The composition according to claim 35, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose.
 37. The composition according to claim 35, wherein the binder is 0.5-10% based on the total weight of the composition.
 38. The composition according to claim 31, wherein the hydrophobic layer further comprises a plasticizer.
 39. The composition according to claim 38, wherein the plasticizer is 0.1-2% based on the total weight of the composition.
 40. The composition according to claim 38, wherein the plasticizer is selected from the group consisting of castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phthalate, glyceryl triheptanoate, hydroxypropyl cellulose, polyethylene glycol, and triethyl citrate.
 41. The composition according to claim 31, wherein the hydrophobic polymer layer comprises ammonio methacrylate copolymer, hydroxypropylmethylcellulose, ethyl cellulose, or cellulose acetate.
 42. The composition according to claim 31, wherein the nonpareil inert core is an inert sugar core or a microcrystalline cellulose core.
 43. The composition according to claim 42, wherein the core is 30-60% based on the total weight of said composition.
 44. In a method for administering venlafaxine hydrochloride to a patient in need thereof, comprising administering the venlafaxine hydrochloride as an extended release composition to the patient, the improvement wherein the extended release composition is in accordance with claim
 31. 45. A method for preparing an extended release composition in accordance with claim 31, comprising: providing the nonpareil inert core; coating the nonpareil inert core with a layer of the venlafaxine hydrochloride; and coating the venlafaxine hydrochloride layer with the hydrophobic polymer layer.
 46. The composition of claim 29, wherein the hydrophilic polymeric or GMS layer comprises polyvinylpyrrolidone, the hydrophobic polymer is ethyl cellulose and the controlled release layer further comprises a dibutyl sebacate plasticizer.
 47. A pH-independent extended release dosage form having dissolution characteristics that are bioequivalent to those of the venlafaxine hydrochloride dosage form sold under the proprietary name EFFEXOR XR, comprising: venlafaxine hydrochloride in an amount of 30-60% based on the total weight of the dosage form; said venlafaxine hydrochloride being coated on a nonpareil inert core, said nonpareil inert core comprising 30-60% based on the total weight of the dosage form; the venlafaxine hydrochloride being optionally connected to a binder in a binder amount of 0.5-10% based on the total weight of the dosage form; a hydrophilic polymeric or glycerol monostearate (GMS) layer coating said venlafaxine hydrochloride and comprising 0.5-10% based on the total weight of the dosage form; and a controlled release layer coated over said hydrophilic polymeric or GMS layer, said controlled release layer comprising a hydrophobic polymer mixed with a plasticizer, said hydrophobic polymer comprising 2-15% based on the total weight of the dosage form, and said plasticizer comprising 0.1-2% based on the total weight of the dosage form; the parameters being selected so as to control release of the venlafaxine hydrochloride over an approximately 24 hour period in a manner that is bioequivalent to the dissolution characteristics of EFFEXOR XR.
 48. The composition of claim 47, wherein the hydrophilic polymeric or GMS layer comprises polyvinylpyrrolidone, the hydrophobic polymer is ethyl cellulose and the controlled release layer further comprises a dibutyl sebacate plasticizer. 